CA2321369C - Dosing regimens for lasofoxifene - Google Patents

Abstract

Based on lasofoxifene's half-life and potency, the drug may be dosed once per week and achieve a similar effect as if given daily.

Description

=1-Dosina Regimens for Lasofox'rfene This invention relates to extended dosing regimens for the estrogen agonist/antagonist lasofoxifene, (-)-cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydronaphthalen-2-ol, D-tartrate.

Background of the Invention Lasofoxifene and related estrogen agonists/antagonists are disclosed in U.S.
Patent 5,552,412 as effective agents for treaang or preventing diseases and conditions selected from obesity, breast cancer, osteoporosis, endometriosis and cardiovascular disease and hypercholesterolemia in male or female mammals and benign prostatic hypertrophy and prostatic carcinomas in male mammals.
This patent describes formulation and dosing procedures for the estrogen agonists/antagonists as follows:
"The pharmaceutically acceptable acid addition salts of the compounds of this invention may be formed of the compound itself, or of any of its esters, and include the phamnaioeuticaily acceptable salts which are often used in phamnaceutical chemistry. For example, salts may be formed with inorganic or organic acids such as hydrochloric acid, hydrobromic acid, hydrolodic acid, sulfonic acids including such agents as naphthalenesulfonic, methanesulfonic and toluenesulfonic acids, sulfuric acid, nitric acid, phosphoric acid, tartaric acid, pyrosulfuric acid, metaphosphoric acid, succinic acid, formic acid, phthalic acid, lactic acid and the like, most preferable with hydrochloric acid, citric acid, benzoic acid, maleic acid, acetic acid and propionic acid.
It is usually preferred to administer a compound of this invention in the form of an acid addibon sait, as it is cxJStomary in the administration of phamnaceuticals bearing a basic group such as the pyrrolidino ring.
The compounds of this invention, as discussed above, are very often administered in the form of acid addition salts. The salts are conveniently fonned, as is usual in organic chemistry, by -reacting the compound of this inventon with a suitable acid, such as have been described above. The saits are quickly formed in high yields at moderate temperatures, and often are prepared by merely isolating the compound from a suitable acidic wash as the final step of the synthesis. The saR-forming acid is dissolved in an appropriate organic solvent, or aqueous organic solvent, such as an alkanol, ketone or ester. On the other hand, if the compound of this invention is desired in the free base form, it is isolated from a basic final wash step, according to the usual practice. A preferred technique for preparing hydrochlorides is to dissolve the free base in a suitable solvent and dry the solution thoroughly, as over molecular sieves, before bubbling hydrogen chloride gas through it.
The dose of a compound of this invention to be administered to a human is rather widely variable and subject to the judgement of the attending physician. It should be noted that it may be necessary to adjust the dose of a compound when it is administered in the form of a salt, such as a laureate, the salt forming moiety of which has an appreciable molecular weight. The general range of effective administration rates of the compounds is from about 0.05 mg/day to about 50 mg/day. A
preferred rate range is from about 0.25 mg/day to 25 mg/day. Of course, it is often practical to administer the daily dose of compound in portions, at various hours of the day.
However, in any given case, the amount of compound administered will depend on such factors as the solubility of the active component, the formulation used and the route of administration.
The route of administration of the compounds of this invention is not critical.
The compounds are known to be absorbed from the alimentary tract, and so it is usually preferred to administer a compound orally for reasons of convenience.
However, the compounds may equally effectively be administered percutaneously, or as suppositories for absorption by the rectum, if desired in a given instance.
The compounds of this invention are usually administered as pharmaceutical compositions which are important and novel embodiments of the invention because of the presence of the compounds. All of the usual types of compositions may be used, including tablets, chewable tablets, capsules, solutions, parenteral soluaons, troches, suppositories and suspensions. Compositions are formulated to contain a daily dose, or a convenient fracdon of daily dose, in a dosage unit, which may be a single tablet or capsule or convenient volume of a liquid.
Any of the compounds may be readily formulated as tablets, capsules and the like; it is preferable to prepare solutions from water-soluble salts, such as the hydrochloride saft.

In general, all of the compositions are prepared according to methods usual in pharmaceutical chemistry.
Capsules are prepared by mixing the compound with a suitable diluent and filling the proper amount of the mixture in capsules. The usual diluents include inert powdered substances such as starch of many different kinds, powdered cellulose, especially crystalline and microcrystalline cellulose, sugars such as fructose, mannitol and sucrose, grain flours and similar edible powders.
Tablets are prepared by direct compression, by wet granulation, or by dry granulation. Their formulations usually incorporate diluents, binders, lubricants and disintegrators as well as the compound. Typical diluents include, for example, various types of starch, lactose, mannitol, kaolin, calcium phosphate or sulfate, inorganic salts such as sodium chloride and powdered sugar. Powdered cellulose derivatives are also useful. Typical tablet binders are substances such as starch, gelatin and sugars such as lactose, fructose, glucose and the like. Natural and synthetic gums are also convenient, including acacia, alginates, methyicellulose, polyvinylpyrrolidine and the like. Polyethylene glycol, ethylcellulose and waxes can also serve as binders.
A lubricant is necessary in a tablet formulation to prevent the tablet and punches from sticking in the die. The lubricant is chosen from such slippery solids as talc, magnesium and calcium stearate, stearic acid and hydrogenated vegetable oils.
Tablet disintegrators are substances which swell when wetted to break up the tablet and release the compound. They include starches, clays, celluloses, algins and gums. More particularly, com and potato starches, methylcellulose, agar, bentonite, wood cellulose, powdered natural sponge, cation-exchange resins, alginic acid, guar gum, citrus pulp and carboxymethylcellulose, for example, may be used as well as sodium lauryl sulfate.
Tablets are often coated with sugar as a flavor and sealant, or with film-forming protecting agents to modify the dissolution properties of the tablet.
The compounds may also be formulated as chewable tablets, by using large amounts of pleasant-tasting substances such as mannitol in the formulation, as is now well-established in the art.
When it is desired to administer a compound as a suppository, the typical bases may be used. Cocoa butter is a traditional suppository base, which may be modified by addition of waxes to raise its melting point slightly. Water-miscible suppository bases comprising, particularly, polyethylene glycols of various molecular weights are in wide use.

The effect of the compounds may be delayed or prolonged by proper formulation. For example, a slowly soluble pellet of the compound may be prepared and incorporated in a tablet or capsule. The technique may be improved by making pellets of several different dissolution rates and filling capsules with a mixture of the pellets. Tablets or capsules may be coated with a film which resists dissolution for a predictable period of time. Even the parenteral preparations may be made long-acting, by dissolving or suspending the compound in oily or emulsified vehicles which allow it to disperse only slowly in the serum.

The active ingredient may be usually administered once to four times a day with a unit dosage of 0.1 mg to 50 mg in human patients, but the above dosage may be properly varied depending on the age, body weight and medical condition of the patient and the type of administration. A preferred dose is 0.25 mg in human patients. One dose per day is preferred.*

Summary of the Invention We have now found that contrary to the teaching of U.S. Patent 5,552,412, that because of a long biological half-life, high potency and favorable safety factors it is possible to dose lasofoxifene once per a period of 7-30 days by oral delivery and achieve equivalent effect as if the drug were administered on a daily basis.

The invention provides a novel pharmaceutical composition in a dosage unit form for maintaining a safe, effective blood level of an estrogen agonist/antagonist for an extended period of time which comprises *Emphasis added (a) an oral dose which is of sufficient quantity to maintain the effective blood level for the extended period of time and (b) a pharmaceutically acceptable carrier.

5 Preferably the estrogen agonist/antagonist is lasofoxifene.

Preferably the extended period of time is 7 days.
Also preferably the quantity is 0.8 to 10.0 mg per dose.

In a preferred aspect of the invention, there is provided a pharmaceutical composition in a unit dosage form comprising (-)-cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydronaphthalen-2-ol or a pharmacologically acceptable salt thereof, and a pharmaceutically acceptable carrier, wherein a single dose of the composition results in a blood concentration of (-)-cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydronaphthalen-2-ol or a pharmacologically acceptable salt thereof of greater than about 0.3 ng/ml over an extended period of time in a patient in need thereof, and wherein the extended period of time is from about seven days to about thirty days.

Another aspect of the present invention provides a commercial package containing the novel pharmaceutical composition and comprising a written matter which describes that the pharmaceutical composition should be taken by a patient once per the extended period of time.

5a Detailed Description of the Invention The prior art, for example U.S. Patent 5,552,412, teaches that lasofoxifene and related compounds should be administered frequently in small doses. Doses as low as 0.1 mg four times per day are suggested for human patients.

We have now unexpectedly found that a single dose of 0.8 mg of lasofoxifene administered to healthy women resulted in an initial blood level of 0.7 ng/ml within a few hours.
Levels declined slowly thereafter to a concentration of about 0.3 ng/ml after 168 hours (1 week). 0.3 ng/ml is considered to be a therapeutic effective dose.

Doses from 10 to 20 mg of lasofoxifene are acceptable. Such a dose would provide a therapeutically effective dose for up to 30 days (i.e., approximately 4 weeks).
See Table 2.

This dose is particularly desirable for human adult patients.

For a dose for a week, 0.8 to 5 mg of lasofoxifene seems reasonable.

Example 1 Validation of LC-MS-MS Method for Lasofoxifene in Human Plasma A dose of 0.8 mg of lasofoxifene was administered to 12 healthy, postmenopausal women and blood sampler were analyzed periodically as shown in Table 1.
A 1.0 ml sample of human plasma was analyzed for lasofoxifene according to CEDRA's Procedure TM-234 (CEDRA's address). Intemal standard used for this procedure was a pentadeuterated lasofoxifene. The plasma sample containing lasofoxifene and the internal standard was extracted with MTBE. Following configuration, the organic layer was transferred to another tube and evaporated. An aliquot of the reconstituted sample extract was then injected onto a SCIEX
API10"Pl's LC-MS-MS instrument equipped with a short ion exchange HPLC column. Peak areas of the m/z 414-+97.9 daughter ion of lasofoxifene were measured against the peak areas of the m/z 419-497.9 daughter of the intemal standard. Quantitation was performed using a 1/x weighted least squares regression line generated from spiked plasma calibration samples.
Plasma levels of lasofoxifene for 168 hours are shown in Table 1 below.
Example 2 The procedure of Example 1 was repeated with a dose of 10 mg lasofoxifene administered to 8 healthy post menopausal women. Plasma levels for lasofoxifene are shown for 672 hours in Table 2.

Table 1 Mean plasma concentrations of lasofoxifene following oral administration of a single a single dose of 0.8 mg to twelve healthy, post menopausal woman Hours after dosina ng Lasofoxifene Standard Deviation Coefficient of per ml lasma variation .5 0.13 0.10 77 1 0.32 0.09 28 2 0.37 0.06 15 4 0.46 0.10 23 8 0.72 0.13 19 12 0.73 0.14 19 24 0.64 0.11 18 48 0.56 0.10 17 72 0.49 0.08 16 120 0.40 0.07 18 168 0.34 0.10 29 = CA 02321369 2000-09-27 Table 2 Mean plasma concentrations of lasofoxifene following oral administration of a single mg dose to eight healthy, post menopausal woman Hours after dosina ng Lasofox'rfene Standard Deviation Coefficient of per ml plasma variation .5 2.33 1.19 51 1 4.42 0.86 19 2 5.64 1.36 24 4 8.46 2.25 27 8 10.45 1.38 13 12 10.25 1.96 19 24 8.35 1.29 15 48 7.16 0.87 12 72 5.97 1.26 21 120 4.56 0.72 16 168 3.74 0.62 17 216 2.88 0.49 17 264 2.27 0.41 18 336 1.60 0.45 28 408 1.05 0.30 29 480 0.75 0.24 32 576 0.50 0.21 41 672 0.31 0.15 47

Claims (10)

1. A pharmaceutical composition in a unit dosage form for treating or preventing an estrogen-related disease or condition selected from the group consisting of obesity, breast cancer, osteoporosis, endometriosis, cardiovascular disease, hypercholesterolemia, benign prostatic hypertrophy and prostatic carcinoma by oral delivery once per an extended period of time to a human patient in need thereof, the composition comprising the following ingredients:

(a) (-)-cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydronaphthalen-2-ol or a pharmacologically acceptable salt thereof, and (b) a pharmaceutically acceptable carrier, wherein a single dose of 0.8 to 20 mg of the ingredient (a) in the composition results in a blood concentration of (-)-cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydronaphthalen-2-ol or a pharmacologically acceptable salt thereof of greater than about 0.3 ng/ml over the extended period of time, and wherein the extended period of time is from 7 to 30 days.

2. The pharmaceutical composition of claim 1, wherein about 0.8 to about 10.0 mg (-)-cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydronaphthalen-2-ol or a pharmacologically acceptable salt thereof is contained.

3. The pharmaceutical composition of claim 1, wherein about 10.0 to about 20.0 mg (-)-cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydronaphthalen-2-ol or a pharmacologically acceptable salt thereof is contained.

4. The pharmaceutical composition of claim 1, wherein about 0.8 mg (-)-cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydronaphthalen-2-ol or a pharmacologically acceptable salt thereof is contained and the extended period of time is about seven days.

5. The pharmaceutical composition of claim 1, wherein about 10.0 mg (-)-cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydronaphthalen-2-ol or a pharmacologically acceptable salt thereof is contained and the extended period of time is about 30 days.

6. The pharmaceutical composition of claim 1, wherein about 0.8 to about 20.0 mg (-)-cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydronaphthalen-2-ol or a pharmacologically acceptable salt thereof is contained and the extended period of time is about seven to about 30 days.

7. The pharmaceutical composition of any one of claims 1 to 6, wherein the (-)-cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydronaphthalen-2-ol or a pharmacologically acceptable salt thereof is (-)-cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydronaphthalen-2-ol, D-tartrate.

8. The pharmaceutical composition of any one of claims 1 to 7, wherein the human patient is a post menopausal woman.

9. A commercial package comprising:

the pharmaceutical composition of any one of claims 1 to 7, and a written matter describing instructions that the pharmaceutical composition is to be taken orally by a human patient once per the extended time period.

10. The commercial package of claim 9, wherein the human patient is a post menopausal woman.